Glioblastoma (GBM), a primary brain tumor, remains an unmet medical need. The major obstacles to GBM treatment are the accessibility of GBM tumors to drugs through natural physiological and pathobiological barriers like the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB), respectively, and the adequate properties of drugs. In addition, complex pathobiology of GBM, including local invasion and intratumoral heterogeneity represent major challenges to generating effective anti-GBM drugs. The unifying theme of our PPG is the exploitation of local access to brain tumors like GBM to achieve and then maximize therapeutic effect in patients. This local access can be accomplished either by direct loco-regional delivery of drugs into the tumor mass and its vicinity or by disrupting the BBB/BBTB. For example, drugs can be delivered locally through convection-enhanced delivery (CED). The overall hypothesis of this PPG is that we can deliver the next generation of molecularly targeted drug candidates to GBM effectively by either significantly re- designed CED and/or by precision BBB/BBTB disruption. To address this hypothesis, we are developing convection-enhanced thermo-chemotherapy catheter system (CETCS) based on a novel arborizing catheter. Furthermore, the BBB disruption will be tested in two innovative ways using: (i) high-frequency irreversible electroporation (H-FIRE), or (ii) a combined approach of stem cells expressing tumor necrosis factor-? (TNF?), a cytokine with a potential to significantly enhance BBB permeability, under a heat responsive promoter that can be remotely activated using high intensity focused ultrasound (HIFU). We will exploit a unique animal model of spontaneous gliomas in dogs, which is amenable to testing medical devices/surgical procedures, and thus is one of the most valuable tools in addressing our PPG's unifying theme. We will explore our hypothesis in three Specific Aims. In Aim 1, we will generate targeted cytotoxic drugs with an increased access to tumors and/or pathophysiologically important tumor compartments. We will generate targeted drug conjugates with BBB-penetrating chemotherapeutics. In Aim2, we will attempt to bypass the BBB/BBTB by developing CED that addresses critical clinical needs. We will evaluate an arborizing catheter for broad distribution of infusates and accurate saturation of target volume in brain tissue. We will evaluate targeted drugs distribution and efficacy by CETCS for treating spontaneous GBM in a canine model. In Aim 3, we will bypass the BBB/BBTB by induced disruption. This will be achieved with H-FIRE treatment allowing for preferential targeting infiltrating tumor cells. We will assess H-FIRE protocols to combinatorially treat spontaneous gliomas in dogs with targeted cytotoxic agents. We will also examine stem cells engineered to express TNF?. Thus, our PPG proposal represents a combined rational approach of novel therapeutic approaches to improve delivery of unique drug candidates of enhanced access to GBM tumor and its compartments. This program is well suited for rapid translation to clinical settings in a foreseeable future.